National Cancer Institute

at the National Institutes of Health

Pain (PDQ®)

Health Professional Version

Pharmacologic Management

Basic Principles of Cancer Pain Management

The World Health Organization (WHO) has described a three-step analgesic ladder as a framework for pain management.[1] It involves a stepped approach based on the severity of the pain. If the pain is mild, one may begin by prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Potential adverse effects should be noted, particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain persists or worsens despite appropriate dose increases, a change to a Step 2 or Step 3 analgesic is indicated. Most patients with cancer pain will require a Step 2 or Step 3 analgesic. Step 1 can be skipped in favor of Step 2 or Step 3 in patients presenting at the onset with moderate-to-severe pain. At each step, an adjuvant drug or modality such as radiation therapy may be considered in selected patients. WHO recommendations are based on worldwide availability of drugs and not strictly on pharmacology.

Analgesics should be given “by mouth, by the clock, by the ladder, and for the individual.”[1] This requires regular scheduling of the analgesic, not just as needed. In addition, rescue-doses for breakthrough pain need to be added. The oral route is preferred as long as a patient is able to swallow. Each analgesic regimen should be adjusted for the patient’s individual circumstances and physical condition.

Acetaminophen and Nonsteroidal Anti-inflammatory Drugs

NSAIDs are effective for relief of mild pain and may have an opioid dose–sparing effect that helps reduce side effects when given with opioids for moderate-to-severe pain. Acetaminophen is included with aspirin and other NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-inflammatory activity.[2][Level of evidence: I] Side effects can occur at any time, and patients who take acetaminophen or NSAIDs, especially elderly patients, should be followed up carefully.[3-5] There is growing debate about whether NSAIDs are useful and have significant opioid-sparing effects. One meta-analysis [6] suggests that the usefulness of NSAIDs is limited and that they do not significantly spare opioid doses. Another study suggests that NSAIDs are useful and reduce the need for opioid dose increases; however, only patients with pain progression after 1 week of opioid stabilization were selected for the study.[7][Level of evidence: I] Patients taking NSAIDs are at risk for platelet dysfunction that may impair blood clotting. Table 1 lists NSAIDs with minimal antiplatelet activity.

The coxibs are a subclass of NSAIDs designed to selectively inhibit cyclooxygenase-2 (COX-2).[8] Development of these drugs was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and that COX-1 was the source of the same prostaglandins in gastric epithelium, with the potential advantage of less gastrointestinal ulceration and bleeding and the absence of platelet inhibition over traditional NSAIDs. Direct comparisons between COX-2 inhibitors are few. A systematic meta-analysis of COX-2 inhibitors compared with traditional NSAIDs or different COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain after minor and major surgical procedures and have a longer duration of action after dental surgery. Rofecoxib was found to provide superior analgesic effect compared with celecoxib, 200 mg. There were insufficient data to comment on toxicity.[9][Level of evidence: I]

There are three coxibs that were approved by the U.S. Food and Drug Administration (FDA): celecoxib, rofecoxib, and valdecoxib. On September 30, 2004, rofecoxib was withdrawn from the market after a study demonstrated that subjects in a colon cancer prevention trial who took the drug at higher-than-typical doses on a long-term basis had a significant increase in the incidence of serious thromboembolic complications. The question that remains unanswered is whether the increased risk applies to all COX-2 inhibitors, with the caution that the burden of proof rests with those who might claim that this is a problem for rofecoxib alone and does not extend to other coxibs.[8,10] On April 7, 2005, valdecoxib was withdrawn from the market. FDA is also asking manufacturers of all marketed prescription NSAIDs, including celecoxib (Celebrex), to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular events and/or the serious, potentially life-threatening gastrointestinal bleeding associated with use of these drugs.

Dosage

Use patient response to determine the effective dosing interval for aspirin, acetaminophen, and other NSAIDs listed in Table 1. When pain relief is not attained with the maximum dosage of one NSAID, try other drugs within this category before abandoning NSAID therapy.

Route of administration

Use readily available oral tablets, capsules, or liquid. During intervals of nausea and vomiting, use suppositories, unless the nausea is NSAID related. Ketorolac tromethamine is the only NSAID available for parenteral use.

Observe patients carefully for adverse effects, which range from mild gastrointestinal discomfort to more serious problems, including the following:

Gastric ulceration.

Hepatic dysfunction.

Myocardial infarction.

Renal failure.

Because both NSAIDs and other drugs (e.g., warfarin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfonamide-containing drugs) are highly protein-bound, there is potential for altered efficacy or toxicity when they are given simultaneously.

aOnly the nonsteroidal anti-inflammatory drugs (NSAIDs) listed here have FDA approval for use as simple analgesics, but clinical experience has also been gained with other drugs.

bAcetaminophen and NSAID dosages for adults weighing less than 50 kg should be adjusted for weight.

cAcetaminophen lacks the peripheral anti-inflammatory and antiplatelet activities of the other NSAIDs.

dThe standard against which other NSAIDs are compared. May inhibit platelet aggregation for longer than 1 week and may cause bleeding. Aspirin is not recommended for pain in children.

eMay have minimal antiplatelet activity.

fAdministration with antacids may decrease absorption.

gUse limited to 5 days or fewer.

hCoombs-positive autoimmune hemolytic anemia has been associated with prolonged use.

iHas the same gastrointestinal toxic effects as oral NSAIDs.

Enteral Medications

acetaminophenc

50 mg q4h; max dose is 400 mg in 24 h (PO)

10–15 mg/kg q4h; max dose is 75 mg/kg total in 24 h (PO)

975 mg q6h; max dose is 4,000 mg in 24 h (PO)

aspirind

650 mg q4h (PO)

10–15 mg/kg q4h (PO)

975 mg q6h (PO)

15–20 mg/kg q4h (PR)

ibuprofen (Motrin, Advil)

400–600 mg q6h (PO)

5–10 mg/kg q4–6h (PO)

magnesium salicylate (Doan’s, Magan, Mobidin, others)

650 mg q4h (PO)

naproxen (Naprosyn, Aleve)

250–275 mg q6–8h (PO)

5 mg/kg q8h (PO)

naproxen sodium (Anaprox)

275 mg q6–8h (PO)

carprofen (Rimadyl)

100 mg tid (PO)

choline magnesium trisalicylatee (Trilisate)

1,000–1,500 mg q6–8h (PO)

25 mg/kg q6–8h (PO)

choline salicylatee (Arthropan)

870 mg q3–4h (PO)

diclofenac (oral) (Voltaren - 1% topical; Pennsaid - 1.5% topical)

50 mg bid–tid oral; 32 g/d topical

Flector (patch): 1 patch bid

diflunisalf (Dolobid)

500 mg q12h (PO)

etodolac (Lodine)

200–400 mg q6–8h (PO)

fenoprofen calcium (Nalfon)

300–600 mg q6h (PO)

ketoprofen (Orudis)

25–60 mg q6–8h (PO)

ketorolac tromethamineg (Toradol)

10 mg q4–6h to a maximum of 40 mg/d

IV administration should not exceed 5 days

meclofenamate sodiumh (Meclomen)

50–100 mg q6h (PO)

mefenamic acid (Ponstel)

250 mg q6h (PO)

sodium salicylate (Anacin, Bufferin)

325–650 mg q3–4h (PO)

Parenteral Medications

acetaminophen (rectal)

650 mg q4–6h, total 3,900 mg (adults aged >12 y) (PR)

15–20 mg/kg q4h (PR), max dose 75 mg/kg total in 24 h

IV acetaminophen

1,000 mg q6h (IV) (adults)

15 mg/kg max (IV), 75 mg/kg in 24 h (children aged <13 y)

ketorolac tromethamineg,i (Toradol)

60 mg initially, then 30 mg q6h (IV)

IV administration should not exceed 5 days

Opioids

Opioids, the major class of analgesics used in management of moderate-to-severe pain, are effective, are easily titrated, and have a favorable benefit-to-risk ratio.

The predictable consequences of long-term opioid administration—tolerance and physical dependence—are often confused with psychological dependence (addiction) that manifests as drug abuse. This misunderstanding can lead to ineffective prescribing, administering, or dispensing of opioids for cancer pain. The result is undertreatment of pain.[11]

Clinicians may be reluctant to give high doses of opioids to patients with advanced disease because of a fear of respiratory depression. Many patients with cancer pain become opioid tolerant during long-term opioid therapy. Therefore, the clinician’s fear of shortening life by increasing opioid doses is usually unfounded.

Opioid types

Opioids are classified as full morphine-like agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their activity at these receptors. The benefits of using opioids and the risks associated with their use vary among individuals.

Morphine is the most commonly used opioid in cancer pain management, largely for reasons of availability and familiarity;[12] however, it is useful to be familiar with more than one type of opioid. Wide interindividual variability in response to both the analgesic and adverse effects of opioids is recognized.[13] Some patients may not experience adequate pain control despite appropriate dose adjustments, while others may develop intolerable adverse effects to one particular opioid (see below). Alternative opioids include hydromorphone, oxycodone, oxymorphone, methadone, and fentanyl. Knowledge of several medications and formulations gives the caregiver much more flexibility in tailoring a regime to a particular patient’s needs.

Short-acting opioids are generally recommended when opioid therapy is being initiated for the first time or when patients are medically unstable or the pain intensity is highly variable. Once stable, patients can be switched to a controlled-release or slow-release formulation. This is more convenient and promotes compliance. (Refer to Table 3 in the Principles of Opioid Administration section of this summary for more information.)

Full agonists

Morphine, hydromorphone, codeine, oxycodone, oxymorphone, hydrocodone, methadone, levorphanol, and fentanyl are classified as full agonists because their effectiveness with increasing doses is not limited by a ceiling. Full agonists will not reverse or antagonize the effects of other full agonists given simultaneously.

Morphine

The most commonly used opioid, morphine, is readily available in several forms, including sustained-release (8–24 hours duration of effectiveness) formulations for oral administration.

Other agonists

For the patient who experiences dose-limiting side effects with one oral opioid (e.g., hallucinations, nightmares, dysphoria, nausea, or mental clouding), other oral opioids should be tried before abandoning one route in favor of another.

Methadone is a synthetic opioid agonist that has been reported to have a number of unique characteristics. These include excellent oral and rectal absorption, no known active metabolites, prolonged duration of action resulting in longer administration intervals, and lower cost than other opioids. Methadone is available as a pill, an elixir, and for parenteral use. Methadone has an average oral bioavailability of approximately 80% (range, 41%–99%).[30]

Morphine is the international gold standard for first-line treatment of cancer pain. Methadone, however, can be considerably less expensive than existing rapid-release or sustained-release morphine or other opioid options. A randomized trial of 103 patients compared the effectiveness and side effects of morphine and methadone as first-line treatments for cancer pain. The outcome of successful pain management was similar for both groups; however, there were significantly more opioid-related dropouts in the methadone group. This study did not demonstrate superior analgesic effectiveness or overall tolerability of methadone over morphine as a first-line treatment for cancer pain. Despite this finding, the authors of this report suggested that study limitations did not allow definitive conclusions that methadone could not be a useful first-line opioid. Further research exploring other doses and schedules of methadone should still be explored.[31][Level of evidence: I]

Because of its long and unpredictable half-life and relatively unknown equianalgesic dose as compared with other opioids, methadone has been generally used by pain specialists with experience in its use. The utility of methadone in cancer pain and difficult cancer pain syndromes such as neuropathic pain has become more widely appreciated and has gained increasing acceptance for use in hospital and hospice settings and by clinicians who are not pain specialists.[32][Level of evidence: II] The methadone preparation widely used in the United States is a racemic mix of the d-isomer and l-isomer of methadone. The d-isomer has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor and may be beneficial in controlling neuropathic pain.

Another controversy related to methadone is the concern that this drug may be associated with a prolonged QTc interval and may lead to torsades de pointes and ventricular arrhythmia. A number of studies have raised this concern. A series of 132 patients taking methadone revealed statistically significant mean increases in QTc of 10.2 to 13.2 milliseconds, yet no episodes of torsades de pointes were reported.[33][Level of evidence: III] This result raises the issue of the clinical significance of this effect. In another retrospective review of 520 patients treated with methadone for cancer pain, no change in QTc was seen in the 56 patients who had electrocardiograms 3 months before and after starting methadone.[34,35] Another study of 100 cancer patients revealed a baseline electrocardiogram in 28%, with only one demonstrating a clinically significant increase in QTc at week 2.[36] Avoidance of concomitant medications that prolong QTc interval [37] or that share common metabolism pathways with methadone [34] is recommended. In high-risk situations, clinicians could consider electrocardiogram monitoring and other clinical precautions such as correcting electrolyte abnormalities.

When converting from another opioid to methadone, the calculated equianalgesic dose ratio of methadone varies depending on the oral morphine-equivalent daily dose (MEDD) of the previous opioid.[38][Level of evidence: II];[22][Level of evidence: III] One guideline for choosing an appropriate initial dose of methadone based on the oral MEDD of the previous opioid is shown in Table 2. For example, a patient who has been using sustained-release morphine at 80 mg every 8 hours (240 mg/d) would be appropriately switched to methadone at a dose of 10 mg every 8 hours (30 mg/d, an 8:1 conversion ratio). In contrast, a patient who is taking sustained-release morphine at a total daily dose of 60 mg/d might be switched to an oral methadone dose of 5 mg every 8 hours (15 mg/d, a 4:1 conversion ratio).

bGreat caution must be used when converting to methadone when very high opioid doses have been used. Often, only a portion of the total opioid dose is converted initially, with further conversions taking place over several days to weeks.

<30

2:1

30–99

4:1

100–299

8:1

300–499

12:1

500–999

15:1

>1,000

20:1 or greaterb

To be conservative, one might estimate that methadone is roughly twice as potent when administered via IV versus oral administration. Thus, a patient with well-controlled pain on a stable oral methadone dose of 10 mg every 8 hours might be given IV methadone at an initial dose of 5 mg every 8 hours if IV use is necessary. Subcutaneous use of methadone may cause skin irritation in some patients but has been used successfully.

In addition to the method described in Table 2, several methods of switching to methadone have been proposed.[22,40,41][Level of evidence: III];[42,43][Level of evidence: II];[44] Some rely on patient-controlled analgesia with fixed doses and flexible intervals, some require fixed intervals and fixed doses, while others stagger the conversion over a few days. Whatever method is chosen, this kind of switch can be safe and effective as long as regular assessments are provided over time, and there is an appreciation of the equianalgesic dose ratio of methadone to morphine in opioid-tolerant patients.

One approach calls for a gradual switch over 3 to 5 days to decrease the risk of relative overdosing. An equianalgesic dose of methadone is first calculated, using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., methadone is approximately ten times more potent than morphine). The caveat in using a ratio of 10:1 is that variations in ratios have been noted, depending on the dose of the previous opioid. The ratio may be much higher (12:1 or even higher) in patients being switched from high doses of morphine to methadone. The following example is given to illustrate this method:

A patient who is on the equivalent of 450 mg/d of oral morphine (quick-release morphine 75 mg orally every 4 hours) needs to be switched to methadone. Using a ratio of 10:1, the predicted equivalent daily oral dose of methadone, once the switch is completed, will be 45 mg.

On day 1 of the switch, the daily morphine dose is reduced by one-third to approximately 300 mg (morphine 50 mg orally every 4 hours), and one-third of the predicted daily methadone dose is added, divided into three doses per 24 hours (i.e., methadone 5 mg orally every 8 hours). Morphine continues to be given for rescue doses.

On day 2 of the switch, the patient is reassessed. If no problems have developed, the morphine dose is reduced by another third (i.e., morphine 25 mg orally every 4 hours), and the methadone dose is increased by another third (i.e., methadone 10 mg orally every 8 hours).

On day 3 of the switch, the patient is reassessed.

If there are complications such as significant somnolence, but the pain is still not under good control, the methadone dose is increased to 15 mg every 8 hours, and the morphine is discontinued.

A rescue dose of methadone or a short half-life opioid is added, as needed. The rescue dose is calculated at 5% to 15% of the total daily dose.

If the patient has good pain control but shows signs of relative overdosing (e.g., significant somnolence), the methadone dose is not increased (i.e., it remains at the day 2 level or may even be decreased, if needed), and the morphine is discontinued.

This approach calls for the previous dose to be discontinued and a single fixed-dose of methadone to be given at the start, calculated using an equianalgesic dose ratio of morphine to methadone of 10:1 (i.e., morphine 10 mg being roughly equivalent to 1 mg of methadone), but to a maximum of 50 mg of methadone per dose. After the initial single priming dose, the same dose is administered every 3 hours as needed. When the clinician observes the patient's demand for rescue doses reduces or stabilizes (indicating steady-state being reached), which is usually on day 4 to 7, the daily requirement is recalculated and the dose is given every 8 to 12 hours.

In this method, an opioid-naïve patient is started on 3 to 5 mg of methadone every 8 hours, and a nonnaïve patient is started on a dose of methadone that is equivalent to 50% of the estimated daily morphine dose. These doses are initially given for 3 days. Once the patient has acceptable pain relief for 6 to 8 hours, the dose is changed to a single fixed dose once a day and rescue doses are given as needed. This method is probably best suited for opioid-naïve patients (in relatively unlikely situations where more frequently used opioids such as morphine are not available) or patients who are, for one reason or another, being switched from relatively low doses of morphine or other opioids.

This method is suggested when patients are being switched from high equivalent daily doses of morphine (>600 mg/d orally). The morphine or other opioid the patient is receiving is stopped. Methadone at a dose of 5 to 10 mg orally is started every 4 hours and rescue doses of 5 to 10 mg every hour are allowed as needed. On the second to third days of the switch, the methadone dose is increased by up to 30% every 4 hours until sufficient pain relief is achieved and no significant adverse effects are noted. After exactly 72 hours following the switch to methadone, the dose is changed from every 4 hours to every 8 hours, and the interval of rescue doses is increased to every 3 hours as needed at the same single dose as established on days 2 to 3. The dose can then be increased by up to 30% if further upward titration is required.

In some countries, there are restrictions on the ability of physicians to prescribe methadone that do not apply to other opioids. In the United States, this pertains to methadone for maintenance of addiction. Methadone is not restricted when used for pain management; however, physicians should carefully document the use of methadone.[45] It should be noted that ratios are different for switching from methadone to a morphine-like opioid.[22]

Meperidine (Demerol)

Useful for brief courses (a few days) to treat acute pain, meperidine is not recommended in treating persistent cancer pain because of its short duration of action (2.5–3.5 hours) and its neurotoxic metabolite, normeperidine. Accumulation of this metabolite, particularly when renal function is impaired, causes central nervous system (CNS) stimulation that may lead to delirium or seizures. Seizures are typically preceded by development of multifocal myoclonus, which can serve as a warning sign.

Tapentadol

Tapentadol is a centrally acting analgesic with a dual mode of action, as a mu-opioid receptor agonist and norepinephrine reuptake inhibitor.[46,47] In 2009, the FDA approved immediate-release tapentadol for the management of moderate to severe pain. In August 2011, the FDA also approved the extended-release formulation of tapentadol for the management of moderate to severe chronic pain. As with other mu-opioid receptor agonists, use of tapentadol may be associated with respiratory depression, sedation, nausea, and constipation. No studies have been published in cancer pain. In the noncancer setting, there appear to be fewer gastrointestinal adverse effects with tapentadol than with oxycodone.[46,47] Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs (this includes serotonin reuptake inhibitors; serotonin and norepinephrine reuptake inhibitors; tricyclic antidepressants; triptans; drugs that affect the serotonergic neurotransmitter system, such as mirtazapine, trazodone, and tramadol; and drugs that impair metabolism of serotonin). Extended-release tapentadol has not been evaluated in patients with a predisposition to seizure disorder.

Tramadol

Tramadol can be considered an atypical opioid analgesic that has a dual action. It is a weak mu-opioid agonist that also inhibits the reuptake of norepinephrine and serotonin.[48][Level of evidence: IV];[49][Level of evidence: I] It is believed that both mechanisms work synergistically to provide analgesic benefit with a potency that is approximately one-tenth that of morphine [50][Level of evidence: II] and approximately equivalent to codeine. The most common side effects reported with tramadol are drowsiness, constipation, dizziness, nausea, and orthostatic hypotension.[48] There is also a risk of precipitating seizures in patients with a previous history or in patients who are receiving medications that could reduce the seizure threshold. The use of other serotonergic medications (e.g., selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) together with tramadol has the potential to increase the risk of the serotonin syndrome. Tramadol is available in short- and long-acting formulations and in fixed combination with acetaminophen. The recommended starting dose of oral tramadol is 50 mg 1 or 2 times a day, with gradual titration up to a maximum of 400 mg/d.[48] There is also the option of using tramadol via the rectal or subcutaneous route in patients who are unable to tolerate oral medication.[51][Level of evidence: I];[52]

Partial agonists

Partial agonists such as buprenorphine are subject to a ceiling effect and are less effective analgesics than full agonists at opioid receptors. A 7-day buprenorphine patch is available; the maximum dose is 20 μg per hour because of the potential for prolonged QTc wave interval.[53]

Mixed agonist-antagonists

Mixed agonist-antagonists block or are neutral at one type of opioid receptor while activating a different opioid receptor. Mixed agonist-antagonists are contraindicated for use in the patient receiving an opioid agonist because they may precipitate a withdrawal syndrome and increase pain. Mixed agonist-antagonists include pentazocine (Talwin), butorphanol tartrate (Stadol), dezocine (Dalgan), and nalbuphine hydrochloride (Nubain). Their analgesic effectiveness is limited by a dose-related ceiling effect.

Principles of opioid administration

Most patients with cancer pain require fixed-schedule dosing to manage the constant pain and prevent the pain from worsening.[54][Level of evidence: II] An Italian study of patients whose baseline pain was well controlled on morphine when admitted to a palliative care unit found that most episodes of breakthrough pain were rapidly controlled with IV morphine equivalent to 20% of the calculated equianalgesic total daily dose. Adverse effects were uncommon.[55][Level of evidence: II] An as-needed rescue dose (breakthrough dose) should be combined with the regular fixed-schedule opioid to control the episodic exacerbation of pain, often referred to as breakthrough pain. When this pain is elicited by an action such as weight-bearing, breathing, or defecation, it is termed incident pain. Rescue or breakthrough doses can be given hourly or more frequently as needed, depending on route of administration, pharmacokinetic properties of the drug, and presence or absence of side effects. The breakthrough dose is generally calculated to be 10% to 20% of the total dose of the fixed schedule.[56][Level of evidence: III] Adherence rates are improved when patients are prescribed around-the-clock opioids compared with as-needed prescribing.[57][Level of evidence: I] Preliminary data suggest that the intensity of incident pain related to bone metastases may be diminished by increasing the dose of the scheduled opioid above that needed for control of baseline pain, while maintaining it below that associated with the development of limiting side effects.[58][Level of evidence: II]

Dosage

The appropriate dosing interval is determined by the opioid and formulation used. The analgesic effects of short-acting oral opioids such as morphine, hydromorphone, codeine, and oxycodone begin within a half hour after administration and last for approximately 4 hours. The dosing interval of these drugs is usually 4 hours. In patients given controlled-release formulations of morphine, hydromorphone, codeine, or oxycodone, relief should begin in 1 hour, peak in 2 to 3 hours, and last for 12 hours (controlled-release codeine is not available in the United States); these formulations are usually prescribed in 12-hour intervals. The analgesic effect of transdermal fentanyl begins approximately 12 hours after the application of the patch, peaks in 24 to 48 hours, and lasts for approximately 72 hours. Patches are therefore changed every 72 hours. In a select group of patients who consistently experience end-of-dose failure despite increases in the patch doses, the dosing interval can be increased to every 48 hours (<10% of patients on fentanyl patches). Transdermal fentanyl is not recommended for control of acute pain or poorly controlled pain because there is a delayed onset of action until reaching steady-state either with new use or with a change in the dose. Patients receiving transdermal fentanyl may be switched to a continuous IV or subcutaneous infusion of fentanyl using a conversion ratio of 1:1 to facilitate more rapid titration.[59][Level of evidence: III]

Dose titration

To date, dose titration is largely patient-driven, as determined by the balance of analgesia with side effects.[60][Level of evidence: II] For example, while morphine dose correlates with peak-and-trough plasma concentrations of a parent drug and its metabolites morphine-3-glucuronide and morphine-6-glucuronide, studies are conflicting with regard to the association between plasma levels of morphine and its metabolites versus analgesia as measured by pain scores.[61][Level of evidence: II] The strong opioid agonists have no maximum dose or ceiling dose. The appropriate dose is the amount of opioid that controls pain with the fewest side effects. Dose titration should continue until good pain relief is achieved or intolerable side effects develop that cannot otherwise be controlled. The goal is to achieve a favorable balance between analgesia and side effects through gradual adjustment of the dose. If analgesic tolerance appears to be occurring, the dose can be increased or consideration given to switching the opioid, especially if higher doses are required.

The severity of the pain and the opioid formulation chosen determine the rate of titration. The dose of immediate-release formulations can be increased on a daily basis if necessary until pain relief is adequate. Among patients receiving relatively low doses of opioids, those with uncontrolled moderate-intensity pain require daily increases of between 25% and 50% to their previous dose, while patients with severe uncontrolled pain may require a higher increase. At higher opioid doses, increases of 20% to 30% would be more prudent. Rapid dose escalation requires close monitoring for both efficacy and side effects. Preliminary data suggest that titration with sustained-release daily morphine is equivalent to titration with immediate-release morphine administered every 4 hours by an expert group of clinicians, but standard practice is to use a short-acting opioid for initial titration.[62][Level of evidence: I]

Occasionally, doses may need to be reduced or, rarely, stopped. This may occur when patients become pain free as a result of cancer treatment, including treatments such as nerve blocks and radiation therapy. Another time to consider reducing the dose is when a patient experiences significant opioid-related sedation that is accompanied by good pain control or when there is metabolite retention in the context of developing and/or worsening renal failure. In situations where interventions achieve complete pain relief, rapid opioid tapering rather than abrupt discontinuation is recommended to avoid opioid withdrawal symptoms.

Different types of opioids

The debate regarding whether any individual opioid causes fewer side effects or is more effective is characterized by much speculation but little clinical evidence. These inconclusive findings have prompted expert working groups of the European Association of Palliative Care to recommend that there is currently little evidence of the clinical superiority of one opioid over another regarding the side-effect profile and/or analgesia.[12,13] Even constipation and other side effects may be positively affected by a switch. Compared with morphine, fentanyl may cause less constipation.[63][Level of evidence: II];[64][Level of evidence: I] Studies suggesting that oxycodone and hydromorphone may cause less nausea and hallucinations than morphine [65] are juxtaposed with other studies that found no significant differences between them.[66-68][Level of evidence: I] One study found that transdermal fentanyl was better tolerated than sustained-release oral morphine and equally effective.[69][Level of evidence: I]

Health professionals should check current recommendations for opioid use in older people, children, people who are cognitively impaired, and known or suspected drug abusers.

Opioid switching (Opioid rotation)

A series of case reports have demonstrated the clinical problem of inadequate pain control with escalating opioid doses in the presence of dose-limiting toxic effects, including hallucinations, confusion, hyperalgesia, myoclonus, sedation, and nausea.[17,23,70-72][Level of evidence: III] It was suggested that these problems could be managed by switching to an alternative opioid, with the result being improved pain management and decreased toxic effects. The improvement with opioid switching, although predominantly demonstrated initially with morphine, has also been reported with other opioids.[73-75][Level of evidence: III];[76][Level of evidence: II] A retrospective review over a 1-year period in a pediatric oncology center supports efficacy of this technique in children, with resolution of adverse opioid effects, largely pruritus, achieved in 90% of patients, while maintaining pain control.[77][Level of evidence: III]

Guidelines for switching from one opioid to another

Guidelines for opioid switching are intended to reduce the risk of relative overdosing or underdosing as one opioid is replaced by another. These guidelines require a working knowledge of an equianalgesic-dose table.[13,78][Level of evidence: IV] The equianalgesic-dose table provides only a broad guide for dose selection when switching from one opioid to another. Wide ranges in interindividual responses to the various opioids have been noted.[78][Level of evidence: IV] Therefore, because of incomplete cross-tolerance in most cases, the calculated dose-equivalent of a new drug must be reduced by 25% to 50% to ensure safety. These figures are based on clinical experience rather than empiric data. The selection of an alternative opioid is largely empirical. There is little clinical evidence to indicate that one opioid has therapeutic superiority over another opioid. A patient, for example, who requires a switch from morphine to another opioid can be switched to hydromorphone, oxycodone, fentanyl, or methadone.[79][Level of evidence: III];[80,81][Level of evidence: II] In one prospective study of 186 cancer patients being treated with morphine, 25% did not respond and required switching to another opioid (oxycodone). The primary reasons for switching included pain, confusion, drowsiness, nightmares, and nausea. Of the 47 patients who required switching to an alternative opioid, 37 (79%) obtained good relief. This result provides beginning evidence for the prevalence of the need to switch, as well as determining the success rate once switching occurs.[82][Level of evidence: II] Patients should be followed closely after a switch and should be reassessed, and the new opioid dose should be adjusted according to the intensity of pain and lack or presence of adverse effects.

Note: The values that appear in Table 3 are NOT recommended starting doses. Opioid doses are highly variable and should be based on the individual’s previous responses and overall condition. Important cautions are contained in the footnotes.

Table 3. Approximate Dose Equivalents for Opioid Analgesicsa

Drug

Oral Dose (mg)

Parenteral Doseb

IV = intravenous; NA = not available.

aPublished tables vary in the suggested doses that are equianalgesic to morphine. Many of these doses are based on clinical consensus rather than well-controlled trials. Clinical response is the criterion that must be applied for each patient; titration to clinical response is necessary. Because there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower-than-equianalgesic dose when changing drugs and re-titrate according to response.

bParenteral dosing includes IV and subcutaneous administration. Onset and duration may vary slightly between these routes; however, doses remain approximately equal. The intramuscular route is not recommended because of variability in uptake of the drug and painful injection.

cCaution: For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to take oral medications. Equianalgesic doses may differ from oral to parenteral doses because of pharmacokinetic differences. Note: A short-acting opioid should normally be used for initial therapy of moderate-to-severe pain.

dCaution: Doses of aspirin and acetaminophen in combination opioid/NSAID preparations must be adjusted to the patient’s body weight.

eTransdermal fentanyl is an alternative. Transdermal fentanyl dosage is not calculated as equianalgesic to a single morphine dosage but is calculated based on a 24-hour opioid dose. See package insert for dosing calculations. Transdermal fentanyl should not be used in opioid-naïve patients.

fTransmucosal and buccal fentanyl are also available and indicated for breakthrough pain, although they are not bioequivalent. Titration of either should be conducted gradually; neither should be used in opioid-naïve patients.

gCaution: Methadone is much more potent than indicated in older published literature. On average, it is ten times more potent than morphine. However, its potency relative to morphine is not linear. When morphine at lower doses (e.g., 30–60 mg/d orally) is switched to methadone, the potency may be 3 to 5 times; when switched from high doses (e.g., >300 mg/d orally), the potency may be 12 times or even higher.

hCaution: The oral to IV dose ratio of methadone is not well established. The IV route is very seldom used, except in cancer centers with pain service familiar with parenteral methadone. Intravenous use of methadone in combination with chlorobutanol is associated with QTc wave prolongation.[37][Level of evidence: III] Subcutaneous administration may cause irritation.

It has been suggested that a less complicated approach than opioid switching would be reassessment of the clinical situation and use of adjuvant analgesics, decreasing the opioid dose if possible, use of medical management for opioid-related side effects, and correction of any contributing metabolic abnormalities.[83,84] Nevertheless, there does appear to be an emerging consensus that opioid switching does have a useful role when pain control remains inadequate with escalating opioid doses and opioid use results in unacceptable opioid-related side effects.[83-85][Level of evidence: IV]

Morphine, as the strong opioid of choice for the management of cancer pain, was used increasingly during the 1970s and 1980s.[86][Level of evidence: IV] Associated with this increasing experience was the clinical observation of the risk of accumulation of morphine metabolites, particularly in the presence of renal impairment. Morphine-6-glucuronide, an analgesic metabolite, was recognized as having a useful role in enhancing analgesia. A number of reports, however, have described seizures, cognitive impairment, nausea, and problems of myoclonus that were associated with accumulation of morphine-6-glucuronide.[86-88][Level of evidence: IV];[89-91][Level of evidence: II];[92,93][Level of evidence: III]

The potential role of morphine metabolites, in particular the ratio of 3-glucuronide to 6-glucuronide in the development of opioid-related toxicity, has been reported. The literature on this issue has been somewhat controversial. There is no disagreement that morphine metabolites increase in the presence of deteriorating renal function; however, there has been conflicting evidence regarding the role and ratios of the metabolites in patients exhibiting both a poor response to increasing morphine doses and associated toxicity.[94-98]

Switching from one opioid to another requires familiarity with a range of opioids and the use of opioid dose-conversion tables.[13,78] When using these ratios, it must be understood that the guidelines should be reviewed and the patients should be monitored more closely during the switching phase. One review has highlighted some important issues related to these tables.[78] Wide ranges in ratios are noted. In the case of methadone, it is much more potent than previously thought (on average ten times more potent), and its equianalgesic dose-ratio compared to other opioids changes according to the dose of the previous opioid; the higher the dose, the higher the ratio. (Note that potency does not denote more effectiveness but denotes the equivalent dose required to obtain the same effect.)

Route of administration

Oral administration is preferred in patients with intact gastrointestinal tracts because it is convenient and usually inexpensive. When patients cannot take oral medications, other less invasive routes (e.g., rectal or transdermal) should be offered. Parenteral methods should be used only when simpler, less demanding, and less costly methods are inappropriate, ineffective, or unacceptable to the patient. In general, assessing the patient’s response to several different oral opioids is advisable before abandoning the oral route in favor of anesthetic, neurosurgical, or other invasive approaches.

Rectal

Use this safe, inexpensive, effective route for delivery of opioids as well as nonopioids when patients have nausea or vomiting. Rectal administration is inappropriate for the patient who has diarrhea, anal/rectal lesions, mucositis, thrombocytopenia, or neutropenia. The use of suppositories is not always culturally acceptable and may not be practical for patients who are obese, have fractures, are physically unable to place the suppository in the rectum, or prefer other routes. When changing from the oral to the rectal route, begin with the same dosage as had been given orally, then titrate as needed.

Transdermal

Fentanyl patches are formulated to provide analgesia lasting up to 72 hours. This preparation is not suitable for rapid dose titration and should be used for relatively stable analgesic requirements when rapid increases or decreases in dosage are not likely to be needed.[99][Level of evidence: I];[100] In the chronic setting, considerable inter- and intraindividual variability may exist in the rate of absorption of fentanyl from transdermal patches in patients receiving a stable dose of transdermal fentanyl.[101,102][Level of evidence: II] Based on a case series, it has been proposed that conversion from transdermal to IV fentanyl using a 1:1 conversion ratio can be safe and effective during acute exacerbations of cancer pain.[59][Level of evidence: III] Although other opioids such as morphine are sometimes compounded into gel form for transdermal application, bioavailability studies demonstrate plasma levels of drug below the level of detection. This practice should not be supported.[103][Level of evidence: I]

Transdermal buprenorphine has been used with success for the treatment of cancer-related pain in Europe, although studies in the United States are not yet published.[104][Level of evidence: I]

Transmucosal/Buccal (fentanyl)

Oral transmucosal fentanyl citrate is used for the relief of breakthrough pain. The lipid solubility of fentanyl allows rapid onset of pain relief. In open-label studies, 72% to 92% of patients found a dose that provided relief from breakthrough pain. Side effects in these studies were consistent with other opioid therapies, including sedation, constipation, stomatitis, and nausea.[105,106][Level of evidence: II] There is growing interest in the use of rapidly acting, highly lipophilic opioids such as fentanyl for the management of difficult breakthrough pain syndromes.[107][Level of evidence: I] An oral transmucosal fentanyl citrate compound for buccal administration has become available for this purpose.[108,109][Level of evidence: I] A double-blind, randomized, placebo-controlled study included 77 patients assigned to dose sequences of fentanyl buccal tablets. In addition, a 130-patient, randomized, double-blind, placebo-controlled trial using fentanyl sublingual spray was performed in opioid-tolerant patients. These studies demonstrated that both fentanyl buccal tablets and fentanyl sublingual spray were efficacious and safe in treating cancer-related breakthrough pain.[110,111][Level of evidence: I][112][Level of evidence: I] Other opioids such as morphine, hydromorphone, and oxycodone are not very lipophilic and therefore not suited for buccal or sublingual administration. In the home setting, opioids are sometimes administered buccally or sublingually with erratic absorption that is likely via the lower gastrointestinal tract.

IV administration provides a rapid onset of analgesia within 2 to 10 minutes. The duration of action after a bolus dose may be shorter than with other routes. This route may be useful if a patient cannot swallow and IV access is established.

The subcutaneous route is as effective as the IV route.[12,117][Level of evidence: I] In some situations, it may even be more convenient, especially if patients are being cared for at home or in a hospice. To facilitate administration via this route, a 25- or 27-gauge butterfly needle can be inserted subcutaneously and left in place for up to 7 days at a time. The anterior thighs, abdomen, upper arms, subclavicular area, and upper back are possible areas for needle insertion. The site should be monitored for signs of infection or irritation and should be changed if these are noted.

The bioavailability of parenterally administered opioids (morphine, hydromorphone, oxycodone, and codeine) is generally two to three times that of the oral route.[118][Level of evidence: II] The dose therefore needs to be halved or decreased by a third when switching from the oral to the subcutaneous and IV routes, respectively (refer to the Approximate Dose Equivalents for Opioid Analgesics table). Opioids administered parenterally may be given either intermittently (usually every 4 hours) or by a continuous infusion. With some exceptions, these two methods appear to be similarly effective.[119][Level of evidence: I]

Other routes

Some studies suggest that the use of inhaled opioids for the management of pain and cancer-related shortness of breath are, with some exceptions, not more effective than systemic administration.[120][Level of evidence: II];[121][Level of evidence: IV] Their absorption via this route is unpredictable.

The intramuscular administration of opioids is not recommended.

Patient-controlled analgesia

Patient-controlled analgesia (PCA) may be used to determine the opioid dose needs when initiating opioid therapy. Once the pain is well controlled, a regular opioid dose can be instituted on the basis of the PCA doses required. This method is contraindicated in patients with cognitive impairment or patients with significant psychological contribution to their pain experience.

Intraspinal

The intraspinal administration of opioids (epidural or intrathecal), especially when combined with a local anesthetic, can be helpful in a very small select group of patients with intractable pain. Use of the epidural or intrathecal route requires skill and expertise that may not be available in all settings. Table 4 presents the advantages and disadvantages of intraspinal administration. Intrathecal opioid therapy has been FDA approved since 1991, and the utility of an implantable drug delivery system (IDDS) to deliver spinal opioids has been compared with comprehensive medical management (CMM) (based on the Agency for Health Care Policy and Research 1994 cancer pain management guidelines) in a randomized trial. There were 202 patients enrolled in this unblinded study. Of the 101 patients randomized to the IDDS, 51 actually received this therapy. Sixteen of these patients (31%) had serious adverse effects. Patients using the IDDS experienced more than 20% reduction in both pain and opioid toxicity more often than the CMM group (P = .02). These data and further analysis in follow-up reports [122,123][Level of evidence: I] suggest that the use of an IDDS delivery system may offer benefit for some cancer patients. More research is needed to determine which subsets of patients will benefit the most from this device, and what the proper timing should be for a trial of intrathecal opioids.[124][Level of evidence I];[125][Level of evidence: II] An open-label study demonstrated that patients with refractory cancer pain experienced better pain relief, fewer opioid-associated side effects, and decreased systemic opioid use when managed with patient-activated intrathecal delivery of morphine via an implanted delivery system. The device was implanted in 119 patients. There were 7 serious adverse events related to the device and 55 serious adverse events related to the implant and delivery-system refill procedures. The FDA denied the application for market approval of this system.[80][Level of evidence: II]

Analgesic properties not demonstrated except for some instances of neuropathic pain.

Added sedation from anxiolytics may compromise neurologic assessment in patients receiving opioids by facilitating the development of delirium.

Sedative/hypnotic drugs alone

barbiturates, benzodiazepines

Analgesic properties not demonstrated.

Added sedation from sedative/hypnotic drugs limits opioid dosing and may facilitate the development of delirium.

Table 6. Routes of Administration To Be Avoided for Treatment of Cancer Pain

Routes of Administration

Rationale for Not Recommending

Intramuscular

Painful.

Absorption unreliable.

Should not be used in children or patients prone to develop dependent edema or patients with thrombocytopenia.

Transnasal

The only drug approved by the FDA for transnasal administration is butorphanol, an agonist-antagonist drug that generally is not recommended. (See opioid agonist-antagonists in Table 5 for more information.)

Side effects of opioids

Clinicians should anticipate and monitor for side effects. The more common adverse effects include nausea, somnolence, and constipation. These should be discussed with patients before starting opioids. Somnolence and nausea are more often encountered with initiation of opioid treatment but tend to resolve within a few days. Clinicians who follow patients during long-term opioid treatment should watch for potential side effects and manage them as the need arises.

Constipation

Anticipate the constipating effects of analgesics. Opioids compromise gastrointestinal tract peristaltic function (a nearly universal side effect). Consequently, stool within the gut lumen becomes excessively dehydrated. The cornerstones of effective prophylaxis, therefore, are measures aimed at keeping the patient well hydrated to maintain well-hydrated stool. Unless there are existing alterations in bowel patterns, such as bowel obstruction or diarrhea, all patients using opioids should be started on a laxative bowel regimen and receive education for bowel management. Patients who do not adequately respond to an aggressive regimen with stool softeners may benefit from the addition of mild osmotic agents (e.g., 70% sorbitol solution, lactulose, milk of magnesia), polyethylene glycol, bulk-forming laxatives (e.g., psyllium) with appropriate orally administered hydration, or mild cathartic laxatives (e.g., senna). Stimulant cathartics (e.g., senna, bisacodyl) may be useful in severely constipated patients; however, they may be relatively ineffective in situations in which stool has become desiccated. Opioid-induced constipation is a frequent cause of chronic nausea and is observed in 40% to 70% of patients receiving opioids.[64][Level of evidence: I] It appears to be dose-related, is characterized by large variability in individuals, and is opioid-receptor mediated via both central and peripheral mechanisms. Opioids extend the gastrointestinal transit time and desiccate the intraluminal content.[126] Unlike nausea, complete tolerance to this effect does not generally develop, and most patients require laxative/stool-softener therapy for as long as they take opioids. A plain x-ray of the abdomen may be helpful in assessing the extent of fecal load.[127]

Initiating a regular laxative regimen emphasizes prevention of opioid-induced constipation. Recommendations regarding laxative treatment have been largely based on clinical experiences and observations. Combinations of a sennoside and a stool softener such as docusate are generally suggested.[128] Reports that fentanyl causes less constipation than oral morphine are interesting but need to be confirmed in further prospective studies.[129][Level of evidence: III];[63][Level of evidence: II] One study demonstrated decreased laxative use in patients on transdermal fentanyl as compared with patients receiving oral morphine treatment.[63] One meta-analysis has revealed a significant difference in favor of transdermal fentanyl for constipation, although this included only three randomized controlled clinical trials.[130] Whether this decrease in laxative usage is clinically significant, however, and whether the decrease relates to the route of administration instead of the opioid type need to be demonstrated. In a single small series, opioid switching of morphine to methadone resulted in a reduction in constipation.[131] Severe opioid-induced constipation may occur. At an extreme it may be present as a severe ileus and pseudo bowel obstruction.[132] As is the case with opioid-induced nausea and constipation, management relies on the use of gastrointestinal prokinetic agents. The use of orally administered opioid-antagonists such as naloxone is being studied.[133][Level of evidence: II];[134][Level of evidence: I] Although the oral bioavailability of these medications is very limited, opioid withdrawal syndromes have been noted when higher doses have been used. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal.[135][Level of evidence: I];[136,137] (Refer to the PDQ summaries on Gastrointestinal Complications, Nausea and Vomiting, and Nutrition in Cancer Care for more information.)

Nausea and vomiting

Nausea and vomiting (emesis) occur in approximately one-third to two-thirds of patients taking opioids.[138][Level of evidence: I];[139,140] Nausea and vomiting are common complications of early exposure to opioids and usually disappear within the first week of treatment. Appropriate antiemetic coverage during the opioid-initiation phase is usually effective in limiting these adverse effects. Nausea alone does not represent an allergic reaction to the opioid. Occasionally, nausea may be experienced when an opioid dose is significantly increased. An antiemetic should be available on an as-needed basis to address this situation.

Three main mechanisms underlie opioid-related nausea and vomiting.[141] The predominant mechanism appears to be stimulation of the chemoreceptor trigger zone, where dopamine is the main neurotransmitter. Another mechanism is reduced gastrointestinal motility, including delayed gastric emptying. Nausea via increased vestibular sensitivity is uncommon.

Multiple antiemetic regimens have been proposed for the management of opioid-induced emesis, but prospective studies comparing one regimen over another are lacking.[141] Metoclopramide or domperidone are generally recommended as first-line agents because they improve gastrointestinal motility and are antidopaminergic.[141,142] Metoclopramide can be administered orally or subcutaneously at doses of 10 mg 4 times a day or every 4 hours, depending on the severity of the nausea. Rescue doses should also be ordered on an as-needed basis. Extrapyramidal-related adverse effects are a potential complication of these medications. The incidence of extrapyramidal reactions is low with domperidone, but this drug is not available in a parenteral formulation. The antihistamines act on the histamine receptors in the vomiting center and on vestibular afferents. They are generally reserved for cases in which vestibular sensitivity, often manifesting as motion-induced nausea, is suspected or for cases in which bowel obstruction precludes the use of gastrointestinal prokinetic agents. Haloperidol may also be used under the latter circumstances. The phenothiazines are an alternative group of antiemetics, but extrapyramidal and anticholinergic adverse effects may be dose-limiting. Chlorpromazine has modest antiemetic activity but a high incidence of sedation, postural hypotension, and anticholinergic adverse effects, whereas piperazine derivatives such as prochlorperazine are stronger antiemetics but cause more extrapyramidal side effects. Anticholinergic side effects also limit the use of anticholinergic agents such as hyoscine hydrobromide (scopolamine) in opioid-induced nausea, particularly in patients with advanced cancer. These patients seem to be more vulnerable to these adverse effects. The role of 5-HT3-receptor antagonists such as ondansetron in ameliorating opioid-induced nausea is not clear.[143][Level of evidence: III]

There appear to be differences between individual patients in the extent to which different opioids cause nausea.[144] These differences form the basis for the strategy of switching from one opioid to another when a particular opioid produces persistent nausea.[145,146] Switching the route, specifically from the oral to the parenteral, has also been suggested, but the study supporting this strategy is small.[147][Level of evidence: II]

Nausea and vomiting can sometimes persist beyond the opioid-initiation phase or occur de novo in patients on long-term opioid treatment. Nausea and vomiting may become chronic in nature. The multicausal nature of the problem needs to be recognized because management is directed at identifying and addressing the various causes.[148] Constipation is a common contributing cause. Chronic nausea has been associated with the accumulation of active opioid metabolites.[93][Level of evidence: III] A number of strategies are suggested to manage chronic nausea, including switching the opioid or decreasing the dose when pain is well controlled. (Refer to the PDQ summary on Nausea and Vomiting for more information.)

Cognitive and other neurotoxic side effects of opioids

Opioid-related neurotoxicity may manifest as cognitive impairment, hallucinations, delirium, generalized myoclonus, hyperalgesia and/or allodynia. Patients who have renal impairment or who are taking higher doses of opioids are at greater risk of developing these side effects. The mechanisms underlying these side effects are unclear, but the opioid metabolites are implicated. When patients present with generalized pain of an unknown source and the opioid dose has been recently increased, hyperalgesia should be considered as a possible diagnosis.[149,150] The etiological contribution of opioids to cognitive impairment and delirium in the cancer patient is often difficult to determine. This is the case particularly in patients with advanced disease in which the baseline vulnerability is associated with multisystem impairment, and the concurrent administration of other psychotropic agents can complicate the assessment of etiology. Nonetheless, opioid-induced cognitive problems have been reported.[151,152] In addition to cognitive impairment within the context of delirium, other effects include myoclonus, hyperalgesia, perceptual disturbance, and seizures.[153] Although the remarkable characteristics, potential severity, and impact of delirium contribute to its dominance in the spectrum of opioid-related cognitive dysfunction, more subtle psychomotor and cognitive opioid effects have been described. Neuropsychological testing has been used to study these more-subtle effects in less-advanced cancer disease,[154][Level of evidence: II] chronic nonmalignant pain,[138][Level of evidence: I];[155][Level of evidence: II] and in healthy volunteers.[156][Level of evidence: I] Collectively, studies of neuropsychological testing have demonstrated somewhat mixed findings,[157] with some detecting opioid-associated impairment in certain aspects of psychomotor or cognitive function [155][Level of evidence: II] and others detecting minimal or no impairment.[138][Level of evidence: I];[154] Clinical experience and some studies suggest that patients become tolerant of the sedating effects that accompany either the initiation of opioid therapy or dose increases,[158][Level of evidence: II] thereby allowing patients who are otherwise physically able, and on stable opioid doses, to safely engage in activities such as driving.[154,159]

Decreased brain cholinergic activity is recognized as one of the potential underlying pathophysiological mechanisms of delirium.[160,161][Level of evidence: II] In the case of meperidine, the anticholinergic activity associated with its active metabolite normeperidine is suspected to be the basis of the cognitive impairment and delirium occurring in association with this opioid.[162,163] Other opioid metabolites have been studied in relation to the generation of neuroexcitatory states in animal laboratory models and delirium in human subjects. A series of animal studies have demonstrated neuroexcitatory states in association with morphine metabolites, morphine-3-glucuronide (M-3-G) [164] and normorphine-3-glucuronide,[165] and the hydromorphone metabolite, hydromorphone-3-glucuronide.[166][Level of evidence: II] In a hospice study of 36 patients with advanced cancer receiving morphine, both M-3-G and morphine-6-glucuronide (M-6-G) levels were studied in relation to the development of side effects, which included nausea and vomiting in 10 patients and cognitive impairment in 9 patients.[167][Level of evidence: II] Creatinine levels, and plasma levels of M-3-G, M-6-G, and dose-corrected M-3-G and M-6-G, were higher in the 19 patients with side effects, suggesting that the elevation of morphine metabolites in association with renal impairment was associated with opioid toxicity, including cognitive impairment. Evidence is extensive demonstrating elevation of opioid-metabolite levels in the setting of renal impairment,[91,98,167][Level of evidence: II];[168,169] and some studies have noted an association with features of neurotoxicity, including cognitive impairment.[152,167][Level of evidence: II] An accumulation of opioid metabolites possibly also occurs during dehydration, which was suggested as a contributory factor in a prospective study of predominantly opioid-related delirium.[170][Level of evidence: II] Switching to another opioid is one strategy for abating the side effects in cases in which accumulation of active metabolites is considered responsible for side effects such as generalized myoclonus, sedation, confusion, or chronic nausea.[26]

Managing cognitive and other neurotoxic effects of opioids

The general management approach to opioid-induced delirium requires a multidimensional assessment to determine the presence of other potentially treatable contributory factors such as dehydration, other centrally acting medications, sepsis, and hypercalcemia.[151,170,171] Clinical experience suggests that the presence of tactile hallucinations and myoclonus,[84] although not exclusively associated with opioid toxicity, raise the suspicion of this cause. A careful assessment can also identify prognostic factors associated with greater difficulty in achieving pain control, the need for higher opioid doses, and consequently greater risk of opioid-induced delirium. (Refer to the PDQ summary on Delirium for more information.) These factors include neuropathic pain, incidental pain, tolerance, somatization of psychological distress, and a positive history of drug or alcohol abuse.[172][Level of evidence: II]

In addition to searching for underlying reversible causes of delirium, the symptomatic management of delirium requires the addition of a neuroleptic agent to control agitation and perceptual or delusional disturbance. Haloperidol is regarded as the drug of choice in this context,[173] and methotrimeprazine and chlorpromazine are considered useful alternatives,[174][Level of evidence: I];[175][Level of evidence: IV] especially when a greater level of sedation is required. Midazolam, a sedating and short-acting benzodiazepine given by continuous infusion, is sometimes necessary, especially in the case of nonreversible delirium.[176][Level of evidence: III] Typical anxiolytics, including lorazepam, can be used to manage comorbid anxiety; however, they may contribute to the occurrence of delirium, so they should be used sparingly, if at all. Early data suggest that some atypical antipsychotics may be beneficial in improving pain control and decreasing opioid requirements in the cancer patient with mild cognitive impairment and/or anxiety. It is unclear whether this benefit is due to a primary effect or to its secondary impact on cognitive impairment and/or anxiety.[177][Level of evidence: II]

The specific management approach to opioid-induced cognitive and other neurotoxic side effects involves either a dose reduction, a change in route, or an opioid switch.[178][Level of evidence: II] If the pain is well controlled, and the cognitive and neurotoxic side effects are not severe, modest opioid dose reduction may be effective. The rationale for switching opioids, commonly referred to as opioid switching, is that a more favorable balance between analgesia and side effects can be achieved, often with a lower dose than that predicted by the conventional analgesic table.[85,151,179] This can reflect incomplete cross-tolerance among opioids in relation to analgesic and other effects.[180] It is also possible that switching to a new opioid could allow for the elimination of potentially toxic opioid metabolites.[181][Level of evidence: III];[151,182] Reduction in opioid dose in the context of an opioid-induced delirium has not been systematically evaluated but is also likely to have beneficial results. Although there is growing evidence to suggest a beneficial role for opioid switching,[146][Level of evidence: II];[181,183] controversy persists over the relative value of opioid switching versus dose reduction.[83]

Cognitive benefit has been reported with the use of methylphenidate in patients receiving a continuous infusion of opioids for cancer pain.[184][Level of evidence: I] The psychostimulant benefit is likely to relate to mitigation of sedation associated with upward dose titration of opioid.[185][Level of evidence: II] Although psychostimulants have been advocated for hypoactive delirium,[186][Level of evidence: IV] any evidence of perceptual or delusional disturbance is considered a contraindication. An open-label study of donepezil, a long-acting selective acetylcholinesterase inhibitor, suggests that it relieves opioid-associated fatigue and sedation in patients who are receiving opioids for cancer pain.[187][Level of evidence: II]

Respiratory depression

Patients receiving long-term opioid therapy generally develop tolerance to the respiratory-depressant effects of these agents. However, concerns about respiratory depression with opioid use remain prevalent among clinicians and patients. Clinicians experienced in end-of-life care recognize that such concerns are generally exaggerated, though empirical research in the area is sparse. One observational study of 30 patients that evaluated the effect of parenteral opioid titration for the control of acute exacerbation of cancer pain showed no association between parenteral opioid titration and hypoventilation at pain control, as measured by change in end-tidal CO2 respiratory rate or oxygen saturation.[188]

When indicated for reversal of opioid-induced respiratory depression, naloxone titrated in small increments or as an infusion should be administered to improve respiratory function without reversing analgesia. The patient should be monitored carefully until the episode of respiratory depression resolves. The opioid antagonists have a short half-life and may have to be given repeatedly until the agonist drug is sufficiently cleared.[189]

Subacute overdose

Perhaps more common than acute respiratory depression, subacute overdose may manifest as slowly progressive (hours to days) somnolence and respiratory depression. Before analgesic doses are reduced, advancing disease must be considered, especially in the dying patient. Generally, withholding one or two doses of an opioid analgesic is adequate to assess whether mental and respiratory depression are opioid related. If symptoms resolve after temporary opioid withdrawal, reduce the scheduled opioid dosage by 25%. If symptoms do not abate, but the patient complains of or exhibits signs of increased pain, or if symptoms referable to opioid withdrawal occur, consider alternative causes for CNS depression and reinstate analgesic treatment. Ongoing assessment is essential to maintain adequate pain relief.

Effects of opioids on sexual function

Reduced libido is a well-known phenomenon for those using heroin or those in a methadone maintenance program; however, clinicians prescribing opioids for pain poorly understand this effect. Early case studies of persons using heroin or methadone described diminished libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea in women.[190-193][Level of evidence: II];[194,195] These effects resolve after the opioid has been discontinued. Other case reports of patients receiving opioids for relief of chronic pain suggest these same findings.[196,197][Level of evidence: III] The long-term effects of reduced testosterone and amenorrhea are not well known. Sexuality is an essential component of quality of life in many patients, including patients with advanced disease.[198][Level of evidence: III] Patients should be assessed for changes in libido and sexual dysfunction. If these changes are distressing to the patient, serum testosterone levels may be obtained. Should the patient seek improvement in libido and performance, treatment is often empirical, keeping in mind that there are many potential causes of changes in sexual function. Treatment includes using nonopioids for pain, adding adjuvant analgesics in the hope the opioid dose may be reduced, or replacing testosterone through injections or a patch (if not contraindicated). More research is needed to understand the relationship between opioids and sexual function, as well as the most effective treatment strategies. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)

Other opioid side effects

Adjuvant Drugs

Adjuvant drugs are valuable during all phases of pain management to enhance analgesic efficacy, treat concurrent symptoms, and provide independent analgesia for specific types of pain.[199][Level of evidence: IV] Adverse drug reactions are common, however, and there are wide interindividual and ethnic differences in drug metabolism.[200][Level of evidence: IV] A survey on symptom severity and management in 593 cancer patients treated for an average of 51 days reported that during this time, anticonvulsants were used in 11.8% of patients, antidepressants in 16%, corticosteroids in 28%, and bisphosphonates in 7.3%.[201][Level of evidence: III] Patients with advanced cancer on palliative medicine services are reported to receive on average five medications for symptom relief, and as a result are at high risk of drug interactions.[200] A further note of caution appears in another study that questioned the concept of opioid-sparing effects of co-analgesics.[202][Level of evidence: III] Nevertheless, adjuvant analgesics have been extensively studied and reviewed in noncancer settings and are generally endorsed as an important intervention in the provision of adequate pain management (see Table 7).[203-206][Level of evidence: IV] Few trials compare adjuvant analgesics in the cancer setting. Not all analgesic agents have been shown to provide clinical benefit when used in conjunction with opioids. In a dose escalation, double-blind, randomized placebo-controlled phase III trial of ketamine in patients with uncontrolled pain on opioids, delivered subcutaneously over 3 to 5 days, versus placebo, there was no difference noted in pain response between arms. There was almost twice the incidence of adverse effects in the ketamine group than was in the placebo arm.[207][Level of evidence: I]

The analgesic benefits of tricyclic antidepressants have been well established and are generally considered first-line therapy for many neuropathic pain syndromes.[203-206,234][Level of evidence: IV] Supporting evidence is strong for amitriptyline and desipramine, and there is endorsement of other newer antidepressants such as maprotiline and paroxetine. Patients with neuropathic pain characterized by continuous dysesthesias are generally believed to be the most likely to benefit from antidepressant management; however, a randomized placebo-controlled study of amitriptyline for neuropathic pain in cancer patients found only slight analgesic benefit with significantly worse adverse effects.[209][Level of evidence: I]

The most common side effects of tricyclic antidepressants are the following:

Constipation.

Dry mouth.

Blurred vision.

Cognitive changes.

Tachycardia.

Urinary retention.

Caution has also been advised in treating patients with cardiac disease, and an electrocardiogram is sometimes recommended as a prudent measure. A slow upward titration is suggested as a good way to avoid side effects.[216][Level of evidence: I]

Anticonvulsants

The group of commonly used anticonvulsants as adjuvant analgesics for neuropathic pain includes carbamazepine, valproate, phenytoin, and clonazepam.[203-206,234][Level of evidence: IV]

Clinical experience with carbamazepine is extensive, but use of this drug is limited in the cancer population because of concern that it causes bone marrow suppression, in particular leukopenia. Other common adverse effects include nystagmus, dizziness, diplopia, cognitive impairment, and mood and sleep disturbance.

Dosing guidelines for phenytoin are similar to those for the treatment for seizures.[203] This drug can be administered using a loading dose, which may be particularly useful in patients with severe pain.

Clonazepam is an anticonvulsant from the benzodiazepine class and is commonly used for treating lancinating or paroxysmal neuropathic pain.[203] The patient must be monitored carefully for drowsiness and cognitive impairment.

Local anesthetics

The use of mexiletine has been described for chronic neuropathic pain.[203,204,206] Side effects are reported as common and include gastrointestinal toxicity, in particular nausea, and CNS side effects such as dizziness. Patients with a history of cardiac disease and those on higher doses are at increased risk of adverse effects, and it is recommended that they receive appropriate cardiac evaluation, including an electrocardiogram.

Corticosteroids

These drugs have achieved wide acceptance in the management of patients with cancer pain. They are indicated as adjuvant analgesics for cancer pain of bone, visceral, and neuropathic origin. Adverse effects include neuropsychiatric syndromes, gastrointestinal disturbances, proximal myopathy, hyperglycemia, aseptic necrosis, capillary fragility, and immunosuppression. The risk of adverse effects increases with the duration of use. As a result, use is often restricted to patients with a limited life expectancy; in addition, once effective pain control is obtained, it is commonly recommended that the dose be tapered as much as possible. Dosage recommendations vary from a trial of low-dose therapy such as dexamethasone 1 to 2 mg or prednisone 5 to 10 mg once or twice daily,[203] to a starting dose of dexamethasone 10 mg twice daily with subsequent tapering to the minimal effective dose.[240]

Another suggested use of corticosteroids is in high doses for short periods in patients with severe pain. This empirical approach recommends a regime of a single bolus of dexamethasone 100 mg IV followed by a small amount given 4 times per day and then tapered over the next few weeks.[203]

Clodronate can be given orally or intravenously. Dosage recommendations are oral clodronate, 1,600 mg/d; or IV clodronate, 600 to 1,500 mg every 2 to 3 weeks. Clodronate is not available in the United States.

Pamidronate has been recommended in the dose range of 60 to 90 mg IV over 2 hours every 3 to 4 weeks; however, pooled results from two multicenter, double-blind, randomized, placebo-controlled trials (n = 350) using pamidronate (90 mg every 3 weeks) failed to demonstrate a benefit for bone pain.[253][Level of evidence: I]

Zoledronic acid is a potent bisphosphonate that can be given as an IV bolus over 15 to 30 minutes in the dose range of 4 to 8 mg; however, the 8-mg dose has been associated with deterioration of renal function.[254-257][Level of evidence: I] The few studies to date suggest administration at 3- to 4-week intervals.[258][Level of evidence: IV]

Ibandronate can be given orally or intravenously. Dosing recommendations are 50 mg orally daily or 6 mg intravenously every 3 to 4 weeks.[259][Level of evidence: I]

Denosumab is a monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL), which is a form of the tumor necrosis factor superfamily. RANKL inhibition prevents osteoclast development and activation, resulting in decreased bone resorption, increased bone density, and reduction in the risk of fractures.[260]

The FDA has highlighted the possibility of severe and sometimes incapacitating bone, joint, and/or muscle pain in patients who are taking bisphosphonates. The musculoskeletal pain may occur within days, months, or years after starting treatment with a bisphosphonate. This pain contrasts with the acute-phase response characterized by fever, chills, bone pain, myalgias, and arthralgias that may sometimes accompany initial administration of intravenous bisphosphonates. The FDA recommends that bisphosphonates be considered a possible cause of severe musculoskeletal pain in patients who present with these symptoms, and health care professionals should consider temporary or permanent discontinuation of the drug. The risk factors and the incidence of the association of this musculoskeletal pain with bisphosphonates remain unknown.[261]

This drug is generally used for spasticity but may also be used for the treatment of neuropathic pain.[203,204,206][Level of evidence: IV] Side effects include drowsiness, dizziness, ataxia, confusion, and nausea and vomiting.

Calcitonin

Although the mechanism by which calcitonin produces analgesia is unknown, historically it has been recommended for the treatment of both bone and neuropathic pain.[203,204,206,247,248] However, a systematic review of randomized double-blind clinical trials assessing the efficacy of calcitonin for control of metastatic bone pain does not support its use.[262][Level of evidence: IV] Because only two of these studies were evaluated as well designed, further research is necessary. The utility of calcitonin for bone pain is unclear.

Clonidine

This traditional antihypertensive can be given via the oral, epidural, or transdermal route and has been recommended as a trial for the management of neuropathic pain. Reported side effects include dry mouth, dizziness and hypotension, sedation, and constipation.[203,204,206][Level of evidence: IV] The maximum recommended dose is 2.4 mg/d.

There is increasing evidence for the importance of NMDA receptors and the possibility that NMDA antagonists may have a role in refractory cancer pain management.[203,263][Level of evidence: III] Ketamine in subanesthetic doses has been used in this setting.[264][Level of evidence: II] The severe psychomimetic adverse effects associated with this treatment, including vivid hallucinations, limit widespread use of ketamine. Coadministration of a neuroleptic or benzodiazepine is recommended to limit the emergence of these effects. Ketamine is generally given subcutaneously at a low starting dose such as 0.1 mg per kg of body weight per hour, with a gradual escalation. Oral ketamine may be a more potent analgesic and have a more favorable side-effect profile than parenteral ketamine.[249][Level of evidence: IV] One study suggests short-duration therapy of a continuous subcutaneous infusion of ketamine over 3 to 5 days. The initial dose is 100 mg/d; if pain control is inadequate, the dose is escalated to 300 mg/d and then to a maximum dose of 500 mg/d. Treatment is continued for 3 days at either the lowest effective dose or 500 mg/d and then discontinued.[263] A systematic review of the benefits and harms of ketamine in managing cancer pain revealed a general lack of studies and small subject numbers,[265,266][Level of evidence: IV] precluding a definitive conclusion on benefits and harms.

Methadone, particularly the racemic mixture, appears to have significant NMDA-antagonist properties.[267] The d-isomer blocks the NMDA receptor and as a result may yield independent analgesic effects and perhaps reverse some analgesic tolerance to the opioid.[268][Level of evidence: II] This may explain the often-unanticipated high potency of methadone.

Dextromethorphan (DM), a commonly prescribed antitussive, may also have NMDA-blocking properties.[268][Level of evidence: II] The clinical significance of this effect, however, is unclear and studies have not been able to determine at what dose these effects may manifest. Oral DM in doses of 60 or 90 mg given preoperatively and postoperatively has been shown to reduce pain intensity and opioid use after orthopedic oncology surgery.[269,270][Level of evidence: I] A randomized, double-blind, placebo-controlled study of 65 patients evaluated the efficacy and safety of DM or placebo with slow-release morphine. The dose of DM was 60 mg 4 times daily, increased after 7 days to 120 mg 4 times daily if tolerated. While the DM group showed somewhat more improvement than the placebo group, the differences were not significant; furthermore, the DM group experienced more toxic effects, particularly dizziness.[271][Level of evidence: I] The authors concluded that DM does not enhance opioid analgesia or modulate opioid tolerance enough in cancer patients to warrant continued use.

Octreotide

Data from a case series of 16 patients with symptomatic hepatic metastases from a variety of nonneuroendocrine primary sites suggest that octreotide palliates pain and improves a variety of quality-of-life indices as measured by the EORTC QLQ-C30 questionnaire.[272][Level of evidence: II]

Under Investigation

Tetrodotoxin

A randomized, placebo-controlled study of subcutaneous tetrodotoxin was carried out on 77 cancer patients across 22 centers in Canada. While results did not achieve statistical significance, there was a trend toward improved pain control. This drug remains experimental and is not commercially available.[273][Level of evidence: I]

Cannabinoids

Cannabis contains more than 60 cannabinoids and has been proposed as a potentially useful treatment for cancer-related pain. A multicenter, double-blind, randomized, placebo-controlled study included 177 cancer patients in a trial of an endocannabinoid system modulator. Positive analgesic effects were observed and merit further study.[274][Level of evidence: I] Another randomized, double-blind, placebo-controlled, graded-dose study was conducted in patients with advanced cancer who had opioid-refractory pain.[275] Patients received either placebo or nabiximols (a cannabinoid formulation) intranasally; nabiximols consisted of 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) per 100-μL spray. Patients were randomly assigned to low-dose (2.7–10.8 mg THC and 2.5–10 mg CBD), medium-dose (16.2–27 mg THC and 15–25 mg CBD), or high-dose (29.7–43.2 mg THC and 27.5–40 mg CBD) levels and were assigned to placebo or active drug within each dose group. A total of 263 patients completed the study, which measured average pain, worst pain, sleep disturbance, and other quality-of-life issues. There was no significant difference in the 30% responder rate, which was the primary analysis. However, in a continuous responder analysis evaluating average daily pain from baseline to end of study, there was a statistically significant greater analgesia for nabiximols (P < .05) versus placebo overall, specifically in the low- and medium-dose groups. Only the high-dose group compared unfavorably with placebo because of adverse events. The authors concluded that nabiximols may be a useful adjunct in treating opioid-refractory pain.[275]

Current Clinical Trials

Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about pain that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Smith GD, Smith MT: Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat. Pain 62 (1): 51-60, 1995. [PUBMED Abstract]

Bartlett SE, Cramond T, Smith MT: The excitatory effects of morphine-3-glucuronide are attenuated by LY274614, a competitive NMDA receptor antagonist, and by midazolam, an agonist at the benzodiazepine site on the GABAA receptor complex. Life Sci 54 (10): 687-94, 1994. [PUBMED Abstract]